Methods for better delivery of active agents to tumors

Abstract

The present invention concerns delivery of agents through the skin. Methods for delivering agents such as bioactive agents are contemplated by the present invention. Specifically, methods for the targeted delivery of agents to one or more areas of the epidermis and thereby, to one or more cancer tumors are described.

What is claimed is: 
     
       1. A method of delivering one or more agents to one or more susceptible tumors of a subject, the method comprising:
 (a) applying one or more delivery devices having between 2 and 50,000 delivery structures to one or more sites of a skin of a subject comprising blood vasculature or lymphatic vasculature, wherein the one or more delivery devices contacts one or more layers of epidermis with one or more reversible permeability enhancers comprising a chemical, physical or electrical permeability enhancer that induces a reversible increase in permeability of one or more barrier cells of the epidermis to at least the one or more agents; 
 (b) administering a total liquid dosage in between 2 and 50,000 sub-doses of the one or more agents at a controlled administration flow rate of from about 0.01 μl/hr to about 100 μl/hr per each of the delivery structures at a total combined controlled administration flow rate of about 0.02 μl/hr/cm2 to about 50,000 μl/hr/cm2 based on a total surface area of the one or more delivery devices that is in contact with a skin of the subject, 
 wherein each sub-dose of the one or more agents is independently administered, in an administering step, to a plurality of independent depths ranging from about 1 μm to about 500 μm beyond a most superficial surface layer of the epidermis of the subject, but still within the epidermis of the subject exhibiting a Gaussian distribution of delivery depths within the epidermis prior to any subsequent diffusion or movement of the one or more agents within the epidermis; and 
 wherein following the administering step, the one or more agents moves or diffuses deeper through the epidermis through a basal layer of the epidermis and into at least a portion of underlying viable dermis to achieve an uptake of a portion of the one or more agents by one or more susceptible blood capillary plexus or lymphatic capillary plexus; and 
 wherein following administration, the permeability of the one or more barrier cells returns to a state prior to contact of the epidermis with the one or more reversible permeability enhancers. 
 
     
     
       2. The method according to  claim 1 , wherein the total liquid dosage of the one or more agents is administered to a plurality of depths within the epidermis consisting only of one or more viable epidermal layers and not a non-viable epidermal layer. 
     
     
       3. The method according to  claim 1 , wherein an average of the plurality of independent depths exhibits a combined average sub-dose delivery depth within the epidermis of about 70 μm to about 175 μm beyond the most superficial surface layer of the epidermis. 
     
     
       4. The method according to  claim 1 , wherein the delivery device comprises an array comprising between 2 and 50,000 of the delivery structures in fluid communication with the one or more agents in a liquid carrier vehicle,
 wherein the delivery device comprises a means for controlling the administration flow rate including at least one component selected from the group consisting of a pump, a fluid delivery rate controller, a syringe, a pen, an elastomer membrane, or any combination thereof; 
 wherein the delivery structures comprise a means for penetrating at least a most superficial layer of the epidermis; and 
 wherein the one or more agents in the liquid carrier vehicle is delivered by the delivery structures to the plurality of independent depths within a viable epidermis of the subject, thereby administering the between 2 and 50,000 sub-doses of the one or more agents. 
 
     
     
       5. The method according to  claim 1  wherein the delivery structures comprise needles. 
     
     
       6. The method according to  claim 1 , wherein the one or more agents is delivered to a tissue volume of the epidermis encompassing the one or more agents prior to any subsequent diffusion or movement of the one or more agents within the epidermis of about 0.7 mm 3  to about 2,500 mm 3 . 
     
     
       7. The method according to  claim 1 , wherein the one or more permeability enhancers is one or more chemical, physical, or electrical permeability enhancers. 
     
     
       8. The method according to  claim 1 , wherein administration of one or more agents achieves a dermal interstitial fluid pressure in the portion of underlying viable dermis beneath a site of administration of about 1 mmHg to about 15 mmHg. 
     
     
       9. The method according to  claim 1 , wherein the one or more agents circulate through the one or more susceptible blood capillary plexus and into or within proximity to one or more susceptible tumors. 
     
     
       10. The method according to  claim 1 , wherein the one or more agents comprise a bioactive agent. 
     
     
       11. The method according to  claim 10  wherein the bioactive agent is useful for treating, retarding progression of, delaying onset of, prophylaxis of, amelioration of or reducing symptoms of a disease comprising the one or more tumors. 
     
     
       12. The method of  claim 10 , wherein a greater concentration of the one or more bioactive agents is delivered to the one or more tumors compared to intravenous, intradermal, or subcutaneous delivery of the one or more bioactive agents. 
     
     
       13. The method according to  claim 1 , wherein a concentration of the one or more agents within one or more susceptible tumors is about 1.25 fold to about 50 fold more than intravenous, intradermal, or subcutaneous delivery of the one or more agents. 
     
     
       14. The method according to  claim 1 , wherein after administration and uptake, the one or more agents circulates through the blood vasculature or lymphatic vasculature to one or more tumors.